Safety and efficacy of S1P receptor modulators for the induction and maintenance phases in inflammatory bowel disease: A systematic review and meta-analysis of randomized controlled trials

Background: Inflammatory bowel disease (IBD) is a chronic inflammatory condition that significantly affects quality of life. Conventional treatments have had limited success. this study evaluates the safety and efficacy of Sphingosine 1-phosphate receptor modulators (S1PrMs) as a potential treatment for IBD. Methods: We conducted a thorough search of published literature on PubMed, EMBASE, and Google Scholar from 2000 to 2023. The inclusion criteria were randomized controlled trials (RCTs) with a target population comprising of IBD patients receiving either S1PrMs or placebo and a comparison of the 2. The statistical analysis was conducted using RevMan (version 5.4). Forest plots presented the results as risk ratios (RR) with a 95% confidence interval. Results: A total of 7 RCTs involving 2471 patients were included. The results were reported for both the induction and maintenance phases of treatment. in the induction phase, the intervention group proved to have a significantly higher incidence of histological remission (RR = 2.67; 95% CI [1.97, 3.60]; P < .00001), endoscopic improvement (RR = 2.06; 95% CI [1.66, 2.56]; P < .00001), clinical remission (RR = 2.23; 95% CI [1.43, 3.46]; P < .0004) and clinical response (RR = 1.37; 95% CI [1.01, 1.84]; P = .04) compared to the placebo group. Outcomes assessed in maintenance phase significantly favored the intervention group over placebo as well, histologic remission (RR = 2.39; 95% CI [1.83, 3.11]; P < .00001), endoscopic improvement (RR = 2.20; 95% CI [1.28, 3.77]; P = .004), clinical remission (RR = 3.03; 95% CI [1.84, 4.99]; P < .0001), and clinical response (RR = 1.74; 95% CI [1.25, 2.42]; P = .001). Conclusion: S1PrMs show promising potential for establishing histologic remission, endoscopic improvement, clinical remission, and corticosteroid-free clinical remission. With more studies and clinical trials, these modulators may become a reliable therapeutic choice for UC patients everywhere.


Introduction
Inflammatory bowel disease (IBD) is a chronic and recurrent inflammatory condition of the gastrointestinal tract, comprising of ulcerative colitis (UC) and Crohn's disease.It is a global rising condition that not only affects the quality of human health but also imposes financial and economic burden on individuals and health systems worldwide.It has affected over 3 million people in the USA and Europe alone and its prevalence is estimated to exceed 0.3% in the many countries of Europe in the upcoming years. [1]onventional treatments, such as aminosalicylates, have shown moderate efficacy in mild to moderately affected patients but their effectiveness is limited in severe cases. [2]lucocorticoids due to their associated adverse effects are not recommended for long-term treatment. [3,4]Other biologic drugs and Janus kinase inhibitors have also limited efficacy among all patients. [5]Therefore, there is a need for more effective therapies for IBD patients with moderate to severe disease. [6]phingosine 1-phosphate receptor modulators (S1PrMs) are emerging as a effective class of drugs for IBD.These compounds target the S1P receptor, a key regulator of inflammation and immune responses, offering a new approach to cope with the disease mechanism.The S1PrMs such as Ozanimod, Etrasimod, Mocravimod, and Amiselimod, have been effective in treating IBD, from moderate to severe patients and improving their health and lifestyle. [6]Also, Ozanimod use has been approved in the US and European Union for the UC, a type of IBD, treatment.It shows high affinity binding to the subtypes of S1P receptors like S1P and S5P, proving it a potential therapeutic option for the various forms of IBD, including UC and Crohn's disease. [7]1PrMs offer several advantages over conventional therapies.They have demonstrated efficacy in moderate to severe cases of IBD, where existing treatments have been less effective.Moreover, the early safety data from preclinical and phase 1 studies support their use as a potential long-term treatment option with improved tolerability. [8]Also, the results from the induction and maintenance phases are favorable for the S1PrMs, the intervention group. [7]The main purpose of this systemic review and meta-analysis is to evaluate the effectiveness, durability and safety of the S1PrMs in the treatment of moderate to severe cases of IBD from the results of recent RCTs.

Data sources and search strategy
This meta-analysis was conducted conclusively with the Preferred Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. [9]Ethical Approval was not needed for this meta-analysis since it involved data collection from previously existing studies.A thorough electronic search encompassing 2000 through May 15, 2023, was performed on PubMed (Medline), EMBASE, and Google Scholar.The investigation was conducted by 2 impartial authors (MAB and ATK) without any restrictions or regard to language.On "clinicaltrials.gov,"we also looked for pertinent published or unpublished clinical trials.In addition, to find potentially relevant studies, we manually searched the reference lists of the included studies and related meta-analyses and review articles.An extensive list of words related to "inflammatory bowel disease," "ulcerative colitis," "Crohn's disease," "ozanimod," "etrasimod," "mocravimod," and " amiselimod" were searched.The detailed search strategy is given in the supplementary file (Table S1, Supplemental Digital Content, http:// links.lww.com/MD/N445).

Study selection
Studies meeting the following criteria were included in this meta-analysis, 1. Study design should be a randomized controlled trial (RCT).2. Target population comprising IBD patients, either ulcerative colitis or Crohn's disease.3. Comparison between any S1PR modulator and placebo.4. Reporting of at least 1 safety or efficacy outcome.
The case reports, review articles, expert opinions, comments, cross-sectionals, editorials, and studies published before the year 2000 were excluded from the analysis.

Data extraction and assessment of study quality
Duplicate studies were deleted from the list after exporting the retrieved articles to Endnote Reference Library Software.The remaining articles were then carefully evaluated by the 2 independent reviewers (MA and AO), and only those articles matching the eligibility requirements were included.Based on the title and abstract, all articles were initially narrowed down.A third reviewer (SK) was involved in settling any discrepancies in the outcome.Data for the baseline characteristics and outcomes were taken from the finalized RCTs and entered into an online Microsoft Excel spreadsheet.Baseline characteristics included were age, BMI, gender, Mayo score, previous ulcerative colitis treatment, and baseline fecal calprotectin.The primary outcomes summarized in Table 1 and included in this meta-analysis are as follows: histological remission, endoscopic improvement, clinical remission, clinical response, serious adverse events, and worsening of ulcerative or ulcerative colitis flare-ups.
ATK employed the Cochrane Collaboration risk of bias method to evaluate the quality of included trials [15] (Fig. S1A,  B, Supplemental Digital Content, http://links.lww.com/MD/N445).

Statistical analysis
The statistical analysis was conducted using RevMan (version 5.4.Copenhagen: Nordic Cochrane Centre, The Cochrane Collaboration, 2014.For the visual presentation of the results, forest plots were computed.The random effects model presented the results as Risk ratios (RR) with a 95% confidence interval.To determine the unique effects of each study on a particular pooled outcome, the outcome was subjected to sensitivity analysis or meta-regression if the Higgin I 2 value reported was >75%.A value of >75% was considered high for I 2 .A P value of .05 was considered significant throughout the analyses.

Publication bias
Publication bias was analyzed via Egger's test using Comprehensive Meta-Analysis version 3.0 (Biostat, Inc., Englewood).A P value >.05 indicated no publication bias in our outcomes (Table 2).Furthermore, funnel plots were computed to assess the publication bias visually, and a symmetrical distribution of studies along the vertical axis also demonstrated the absence of publication bias.Funnel plots are provided in the supplementary file (Fig. S3A-F, Supplemental Digital Content, http://links.lww.com/MD/N445).

Study selection
Extensive research was conducted on various electronic databases: PubMed (4 articles), Google Scholar (237 articles), Embase (202 articles), and ClinicalTrials.gov(5 articles) from 2000 onwards which yielded 243 results after screening.Two independent reviewers screened these articles.Initially, 243 articles were selected based on their titles and abstracts.Considering eligibility criteria, 227 articles were excluded after reviewing the titles and abstracts.Subsequently, the full texts of 16 articles were retrieved for further evaluation.Fifteen of these articles were deemed eligible.Ultimately, a total of 6 studies, 7 randomized control trials [6,12,10,11,13,14] , that met the inclusion criteria were included in our meta-analysis.The Prisma flow diagram, www.md-journal.comas illustrated in Figure 1, guides us through the steps of identification, screening, and selection of articles that meet the study's criteria.

Patients' demographics
The 7 RCTs selected for the statistical analysis comprised 2471 patients (860 in the placebo group, 1611 in the intervention group).The mean age of the patients ranged between 31 and 43 years.Table 3 provides information on baseline characteristics which include: BMI, age, Mayo score, previous treatment for ulcerative colitis, and baseline fecal protein.Table 1 summarizes the 6 primary outcomes which includes: histologic remission, endoscopic improvement, clinical remission, clinical response, serious adverse events, worsening of ulcerative colitis, or ulcerative colitis flare-ups.The details like inclusion/exclusion criteria, primary outcomes, follow-ups, and treatments used in each trial were also reported.Radeke 2020 [13] Placebo (n = 10) Haens 2022 [14] Placebo (n = 39)
Clinical remission was reported as an outcome measure in the maintenance phase in 2 out of 7 studies.The forest plot favored the S1PrM group as compared to the placebo group, and the results were statistically significant (RR = 3.03; 95% CI [1.84, 4.99]; P < .0001;I 2 = 55%).Moderately heterogeneity was reported in these results.

Serious adverse events
All studies showed evidence of serious adverse events as an outcome measure during the induction phase.Pooled analysis revealed that the incidence of serious adverse events is less in the placebo group than in the intervention group, but the results were not statistically significant (RR = 1.25; 95% CI [0.80, 1.94]; P = .33;I 2 = 20%).

Secondary outcomes
The effect sizes of the secondary outcomes analyzed are given in Table 4. Symptomatic remission, endoscopic normalization, mucosal healing, and corticosteroid-free clinical significantly improved in the S1PrM group.However, there were more adverse events, including anemia and nasopharyngitis.Forest plots of secondary outcomes are provided in the supplementary file (Fig. S2A-P, Supplemental Digital Content, http://links.lww.com/MD/N445).

Discussion
IBD, which affects millions of people worldwide, is a difficult condition to manage. [17]The S1P receptor is a critical regulator of immunological responses and inflammation, and S1P receptor modulators target this receptor, providing a novel and promising method to modify the disease process. [18]Ozanimod, etrasimod, mocravimod, and amiselimod have emerged as possible options among the S1P receptor modulators, igniting interest in IBD treatment. [16,19,20]In the context of IBD, the findings of this meta-analysis provide insight into the relative efficacy of these selective S1P receptor modulators.We sought to evaluate the influence of these medications on various clinical outcomes throughout the induction and maintenance stages of treatment by analyzing the data from numerous randomized controlled trials (RCTs).
Seven randomized control trials were found to be eligible for inclusion in this meta-analysis after a thorough search of electronic databases.In the trials, the effects of S1P receptor modulators were studied in UC patients, and Crohn's disease, and variables such as histologic remission, endoscopic improvement, clinical remission, clinical response, major adverse events, and the likelihood of ulcerative colitis worsening were assessed.
To understand more about potential differences between these medicines, a subgroup analysis was performed based on the specific S1P receptor modulator used.
[23] However, a recent multicenter European cohort study assessing disease burden and unmet clinical requirements in persons with moderate-to-severe ulcerative colitis highlighted poor efficacy with conventional therapies. [24]Many patients still do not respond to induction therapy (first non-responders) or lose their response over time (secondary responders) despite the significant increase in treatment alternatives over the past 20 years. [25]ccording to researchers, new doors for treatment are opened because of Sphingosine-1-phosphate modulators that are approved for the treatment of different immunemediated conditions. [26,27]Clinical trials that targeted S1P receptors for inflammatory disorders were successful, and as a result, the non-selective S1P modulator fingolimod was approved for relapsing forms of multiple sclerosis.The basis for creating more selective S1P receptor modulators is provided by our study, which concentrates on selective S1P modulator receptors to reduce the likelihood of significant side effects. [24]This meta-analysis is a valuable addition to evaluate the role of S1P receptor modulator in IBD as the literature is very scarce.
Ozanimod and Etrasimod are considered more effective S1P modulators for Ulcerative Colitis than Mocravimod and Amiselimod due to their efficacy, safety profiles, and mechanisms of action.They have demonstrated improved results in clinical trials, including lowering inflammation and improving mucosal repair, with potentially fewer adverse effects.Furthermore, they may have better pharmacokinetic qualities and targetspecific mechanisms, making them more appropriate for the treatment of Ulcerative Colitis. [25]In a phase II trial in patients with moderate-to-severe UC, a daily dose of 1 mg ozanimod resulted in a higher rate of clinical remission at 8 weeks, the primary endpoint, than placebo, [12] and our study demonstrated that ozanimod and etrasimod significantly contributed to corticosteroid-free clinical remission.According to Lasa et al, [28] ozanimod and infliximab performed superior to other biologics or small-molecule drugs in inducing clinical remission during the induction phase of UC.Dubinsky et al [29] demonstrated that ozanimod performed comparable to ustekinumab but had more favorable infection adverse rates, supporting the finding of our study.Similarly, in an open-label extension trial by Vermeire et al, [16] etrasimod significantly improved the outcomes of ulcerative colitis, including clinical response, clinical remission, and endoscopic improvement.However, in their study, 60% of the patients receiving etrasimod 2 mg reported treatment-emergent adverse events, with worsening ulcerative colitis and anemia being the most common.In our study, although adverse events were reported, the results were not statistically significant.
Our study had several strengths, including the following: Using strict eligibility criteria to choose studies for the meta-analysis improves the relevance and quality of the data included by ensuring that only studies that met specific inclusion and exclusion criteria were considered.All the RCTs included in our meta-analysis were high-quality and multicenter trials, enhancing our findings' reliability.The internal validity of our results is strengthened by low heterogeneity in most of the outcomes.Our meta-analysis is a significant contribution that offers a novel viewpoint on IBD treatment because it focuses on selective S1P receptor modulators in the setting of ulcerative colitis.In both the induction and maintenance phases, subgroup analyses based on S1P receptor modulators (ozanimod, etrasimod, mocravimod, and amiselimod) enable a more nuanced understanding of the efficacy of these drugs individually, providing helpful insights to direct clinical decision-making.

Limitations
Acknowledging a few limitations in our study for a transparent approach is essential.There was some heterogeneity present in our outcomes, so we used random effects instead of fixed, which is used in 0% heterogeneity.The findings may be less generalizable because only RCTs were included.Secondly, some research failed to publish results during the maintenance phase, which might have affected the total results.Despite these drawbacks, the study offers insightful information that should be addressed in follow-up studies to add to the existing literature.

Conclusions
This meta-analysis, in conclusion, offers critical information about the use of selective S1P receptor modulators for treating IBD.S1PrMs show promising potential for establishing histologic remission, endoscopic improvement, clinical remission, and corticosteroid-free clinical remission.These findings are significant in improving IBD management and raising the prospect of better long-term results for disease management.With more studies and clinical trials, these modulators may become a reliable therapeutic choice for UC patients everywhere.

Figure 2 .
Figure 2. (A) Forest plot of clinical remission during the induction phase.(B) Forest plot of histological remission during the induction phase.(C) Forest plot of endoscopic improvement during the induction phase.(D) Forest plot of clinical response during the induction phase.(E) Forest plot of serious adverse events during the induction phase.(F) Forest plot of worsening ulcerative or ulcerative colitis flare-ups during the induction phase.(G) Forest plot of clinical remission during the maintenance phase.(H) Forest plot of endoscopic improvement during the maintenance phase.(I) Forest plot of histological remission during the maintenance phase.CI = confidence interval.

Table 1
Outcome table.